Macrophages play critical roles both as pro-inflammatory cells and as destructive effector cells in non-septic inflammatory diseases such as arthritis, vasculitis, and multiple sclerosis. The objective of this project is to determine the complex sequence of interactions between T cells and macrophages involved in the pathogenesis of autoimmune inflammatory diseases and to identify specific molecules involved that might be useful as therapeutic targets. CD4O:CD4O-ligand interactions have been shown to play a major role in T cell signaling of macrophage activation. Although the macrophage signaling ability of T cells is reduced in CD4OL-knockout mice, it is not absent. This study will examine established T cell clones generated from CD4OL-knockout mice to identify CD4O-independent signaling of macrophage accessory, inflammatory, and effector function. Transgenic T cells expressing the receptor for myelin basic protein will be used to study the initial interactions between naive T cells and macrophages in the presence or absence of functional CD40:CD4O-ligand interactions. The role of cytokines co-stimulatory for T cells or costimulatory for macrophages in augmenting T cell signaling of macrophage function will also be evaluated.